Midlife Alcohol Consumption and the Risk of Stroke in the Atherosclerosis Risk in Communities Study

Abstract

Background and Purpose

Alcohol consumption is common in the US and may confer beneficial cardiovascular effects at light-to-moderate doses. The alcohol-stroke relationship remains debated. We estimated the relationship between mid-life, self-reported alcohol consumption and ischemic stroke (IS) and intracerebral hemorrhage (ICH) in a biracial cohort.

Methods

We examined 12,433 never and current drinkers in the Atherosclerosis Risk in Communities Study, aged 45-64 at baseline. Participants self-reported usual drinks/week of beer, wine, and liquor at baseline. We used multivariate Cox proportional hazards regression to assess the association of current alcohol consumption relative to lifetime abstention with incident IS and ICH and modification by sex-race group. We modeled alcohol intake with quadratic splines to further assess dose-response relationships.

Results

One-third of participants self-reported abstention, 39% and 24%, respectively, consumed ≤3 and 4-17 drinks/week, and only 5% reported heavier drinking. There were 773 IS and 81 ICH over follow-up (median ~22.6 years). For IS, light and moderate alcohol consumption were not associated with incidence (HR=0.98, 95% CI 0.79-1.21; 1.06, 0.84-1.34) while heavier drinking was associated with a 31% increased rate relative to abstention (HR=1.31, 0.92-1.86). For ICH, moderate-to-heavy (HR=1.99, 1.07-3.70), but not light, consumption increased incidence.

Conclusion

Self-reported light-to-moderate alcohol consumption at mid-life was not associated with reduced stroke risk compared with abstention over 20 years of follow-up in the ARIC study. Heavier consumption increased the risk for both outcomes as did moderate intake for ICH.

INTRODUCTION

Stroke is a leading cause of mortality and disability worldwide, a major contributor to U.S. healthcare costs, and is projected to increase in burden as the population ages.^1-3 As such, continued examination of modifiable risk factors and behaviors that may prevent disease occurrence is needed. One such factor may be alcohol, a prevalent exposure both in the U.S. and worldwide. Seventy percent of U.S. adults report current drinking and more than one-quarter report excessive drinking.^{4, 5}

The relationship between alcohol intake and stroke has been widely studied, yet uncertainties remain; results from observational studies are inconsistent and randomized trials are infeasible. Light-to-moderate alcohol consumption (usually defined as 1-2 drinks per day in the U.S.) may reduce the risk of stroke, but some studies, particularly older ones, have not found beneficial effects.^6-8 Current meta-analyses suggest that moderate intake is protective for ischemic stroke (IS), but not intracerebral hemorrhagic (ICH), with possible differential dose-responses by sex.^6-8 Limitations of our understanding stem from 1) the assessment of alcohol intake late in life, a period that may not reflect the most critical exposure window for disease risk and that may be influenced by other medical conditions developing in later life; 2) alcohol measurement error and misspecification due to variations in drinking patterns; and 3) limited generalizability.^6-15 Furthermore, some studies lack adjustment for lifestyle and socioeconomic factors that may account for protective effects in light drinkers, or combine former and never drinkers in a single referent group. In contrast to the evidence on light-to-moderate intake, consistent and convincing evidence supports the harmful effects of heavy consumption on stroke risk. The precise dose-response relationship, however, is unclear.

Despite the large body of work on alcohol and stroke, few studies have included substantial numbers of minority individuals. Blacks have higher stroke incidence and different drinking patterns from whites and therefore warrant investigation.³ In addition, few studies have accounted for the competing risk of mortality, which may be substantial in prospective studies. Subdistribution hazard estimation is particularly useful to public health scientists interested in assessing risks and benefits of alcohol in a population experiencing competing risks.¹⁶ In our study, we estimated the dose-response relationship between usual, mid-life alcohol consumption and incident stroke among black and white adults in the Atherosclerosis Risk in Communities (ARIC) study, a population-based cohort drawn from 4 US communities.

METHODS

Study Population

The ARIC study is a population-based cohort recruited using probability sampling of adults aged 45-64 years from 4 US communities: Forsyth County, NC; Jackson, MS; suburbs of Minneapolis, MN; and Washington County, MD. The ARIC study design and rationale are described in detail elsewhere.¹⁷ A total of 15,792 participants were enrolled at Visit 1 (1987-1989) and underwent an in-home interview and physical examination, with four additional study visits over the subsequent 25 years. For analysis, we excluded race-ethnicities other than white or black (N= 48), blacks from Minnesota or Washington County (N=55), participants missing alcohol intake (N=106), and those with prevalent stroke (N=284). After these exclusions, the analytic cohort totaled 15,305. We further limited our population to current or never drinkers (N=12,433) because of the heterogeneity in exposure among former drinkers in our population with regard to duration and quantity of consumption and time since cessation.¹²

Alcohol Assessment

Alcohol consumption was measured at baseline using an interviewer-administered questionnaire developed in accordance with the validated Willett 66-item food frequency questionnaire (FFQ).¹⁸ Participants were asked to report whether they currently consumed alcoholic beverages and if so, their usual intake of drinks per week; those reporting values under 0.5 were recorded as ‘0’. Separate intake frequency questions were asked for standard drinks of wine (4-oz), beer (12-oz), and hard liquor (1.5-oz). Total drinks per week was calculated as the sum of standard drinks of each type.

Stroke Definition

Suspected stroke hospitalizations were ascertained by self-report, at study visits, during annual follow-up, and surveillance of local hospital discharge lists. Validation of suspected events and stroke diagnosis were conducted independently by a computer-derived algorithm and a physician reviewer using data abstracted from the medical record; differences were adjudicated by a second physician reviewer. Strokes were classified using criteria adopted from the National Survey of Stroke¹⁹ and required, at a minimum, evidence of sudden or rapid onset of neurological symptoms lasting >24 hours or leading to death in the absence of evidence for a nonstroke cause. Out-of-hospital fatal strokes (N=19) were not validated and were not included. Additional details of stroke subtype classification have been published.²⁰

Covariates

Confounders were identified based on substantive knowledge and directed acyclic graph analysis was used to obtain a minimally sufficient set of adjustment variables: age, sex, race, study center, baseline comorbid conditions, diet score, low-density lipoprotein cholesterol, education, smoking status, and marital status.²¹ Causal intermediates included blood pressure, high-density lipoprotein cholesterol, and atrial fibrillation.

Dietary factors were assessed using an interviewer-administered 66-item FFQ measuring usual intake of foods over the past year. We calculated a diet score as described elsewhere²² based on quintile values for 6 dietary components: percent energy from trans and omega-3 fatty acids, fiber, folate, glycemic load, and polyunsaturated:saturated fatty acid ratio. Physical activity was measured using the Baecke physical activity questionnaire.²³ Baseline medical history included diabetes (self-reported physician diagnosis, fasting glucose ≥126 mg/dL, non-fasting ≥200 mg/dL, or self-reported pharmacologic treatment) and coronary artery disease (electrocardiogram-adjudicated or self-reported myocardial infarction or any of self-reported heart/arterial surgery, coronary bypass, or angioplasty).

Statistical methods

Descriptive statistics for participant characteristics were calculated according to alcohol intake category. Cox proportional hazards regression was used to estimate hazard ratios and 95% confidence intervals for the association between alcohol and incident IS, ICH, and total stroke. Participants contributed person-time until the earliest of: incident stroke, death, loss to follow-up, or end of follow-up on December 31, 2011. The proportional hazards assumption was tested using interaction terms between exposure and time.

Alcohol consumption was categorized as drinks per week by examining the dose-response relationship as well as using a priori values selected to align with prior research and recommended guidelines. Results were robust to different category boundaries and are presented herein as ≤3, 4-17, and 18 or more drinks per week, which reflect our data-informed categorization and cut-points of previous studies.¹⁴ In a second alcohol assessment at year 6, 67% of participants were categorized the same as at baseline. We assessed possible non-linear relationships using quadratic splines and polynomial terms. Knots were selected based on AIC values compared across models with 2, 3, and 4 knots located at percentile values.²⁴ Secondary models for IS were stratified by sex-race group.

In secondary analysis, we estimated sub-distribution hazard ratios (HR_SD) to assess the risk of stroke given the relatively high proportion of death (26%) over follow-up. Cause-specific hazards models, which censor deaths, yield estimates reflecting the relative rate of stroke. HR_SD, on the other hand, reflect the relative risk over a period of time.¹⁶ These were obtained using the SAS macro PSHREG based on the proportional sub-distribution hazards model proposed by Fine and Grey.²⁵ All analyses were conducted using Statistical Analysis Software Version 9.2 (SAS Inc., Cary, N.C.).

RESULTS

Over one-third of the ARIC participants were light alcohol drinkers, consuming ≤3 drinks/week (Table 1). Roughly one-third reported lifetime abstention from alcohol, one-quarter were moderate drinkers of 4-17 drinks/week, and only 5% consumed >18 drinks/week. Women comprised the largest proportion of abstainers and white men accounted for nearly three-quarters of heavier drinkers. Light-to-moderate drinkers were of higher socioeconomic status – in the form of greater educational attainment, more managerial occupations, and higher family income - than heavier drinkers and lifetime abstainers. Current smoking was reported by 46% of heavier drinkers but only 23% of light drinkers. The prevalence proportion of diabetes was low overall (8.6%) and roughly twice as high in abstainers compared with current drinkers. Finally, blood pressure and HDL-C increased across alcohol consumption level.

TABLE 1.

Characteristics of ARIC participants according to self-reported usual alcohol consumption at baseline.^*

	Alcohol consumption, drinks per week
	Lifetime abstainer	Light (≤3)	Moderate (4-17)	Heavier (18+)
Number of participants	3851	4876	3042	664
Person-years	76974.8	99125.5	60479.2	11947.2
Alcohol consumption, median (25th- 75th percentile)
Grams ethanol per week		0 (0-24)	95 (68-151)	317 (277-415)
Glasses per week		0 (0-2)	7 (5-11)	24 (20-30)
Age, years	54.6 (5.7)	53.7 (5.8)	53.8 (5.7)	53.9 (5.8)
Sex-race group
White men	14	34	50	71
White women	40	55	34	11
Black men	8	4	11	17
Black women	38	7	5	2
Educational attainment
<High school	30	13	14	19
High school or vocational	41	45	38	43
College degree or higher	29	43	49	38
Occupation
Managerial	18	29	34	25
Non-managerial	69	59	53	57
Retired	13	13	14	19
Income
<$12,000	22	7	7	10
$12,000-$49,999	65	60	52	60
$50,000+	13	34	41	30
Physical activity index score	2.2 (0.7)	2.5 (0.8)	2.6 (0.8)	2.4 (0.8)
Diet score	12.3 (3.8)	11.8 (3.9)	12.0 (3.8)	12.0 (3.7)
Cigarette smoking
Current	13	23	30	46
Former	16	33	43	43
Never	71	44	27	12
Blood pressure, mmHg
Systolic	124.0 (19.9)	117.9 (17.3)	120.9 (18.4)	127.1 (18.8)
Diastolic	74.5 (11.5)	72.2 (10.6)	74.3 (11.2)	77.0 (11.5)
LDL-c, mg/dL	139.4 (40.7)	136.3 (38.1)	135.3 (39.7)	132.4 (39.8)
HDL-c, mg/dL	37.8 (10.7)	37.0 (10.9)	39.4 (11.7)	40.5 (12.1)
Body mass index, kg/m2	29.0 (6.1)	27.1 (4.9)	26.6 (4.5)	26.7 (4.5)
Coronary artery disease	2	3	3	4
Diabetes	13	7	7	7

^*Population includes never and current drinkers, excluding prevalent strokes, non-white or black, blacks from Washington County or Minnesota, and missing alcohol information for a total N=12,433. Proportions reflect person-time distributions of covariates; all p<0.001. Values are presented as %, or mean (SD), unless otherwise specified.

Over a median follow-up of 22.6 and 22.7 years, respectively, there were 773 IS and 81 ICH. Ischemic stroke incidence rates per 100,000 person-years increased across alcohol intake categories: 251 for ≤3/week, 313 for 4-17/week, 435 for ≥18/week, and 368 for abstainers (Table 2). Estimates were attenuated after adjustment for covariates; most of this attenuation occurred with model 1 covariates. In fully-adjusted Cox models, light and moderate drinking were not associated with IS compared with lifetime abstention (HR=0.98, 95% CI 0.79-1.21; 1.06, 0.84-1.34, respectively; Table 2). Heavier drinking was associated with a 31% increase relative to abstainers (HR=1.31, 0.92-1.86). Confidence intervals for these associations were wide and overlapped the null.

TABLE 2.

Hazard ratios and 95% confidence intervals (CI) for the association of alcohol consumption and IS and ICH

	Alcohol Consumption, drinks per week
	Lifetime abstainer	≤3	4-17	18+
Ischemic stroke
Events	283	249	189	52
Person-years	76,975	99,126	60,479	11,947
Incidence rate per  100,000 PY (95% CI)	367.7 (326.7-412.4)	251.2 (221.4-286.9)	312.5 (270.3-359.5)	435.2 (328.7-566.0)
Hazard ratio (95% CI)
Unadjusted	1	0.68 (0.57-0.81)	0.85 (0.71-1.02)	1.22 (0.91-1.64)
Model 1*	1	0.90 (0.74-1.10)	0.97 (0.78-1.20)	1.17 (0.84-1.63)
Model 2**	1	0.98 (0.79-1.21)	1.06 (0.84-1.34)	1.31 (0.92-1.86)
	Lifetime abstainer	≤3	4+
Intracerebral hemorrhage
Events	31	20	30
Person-years	78,599	100,456	73,711
Incidence rate per  100,000 PY (95% CI)	39.4 (27.3-55.2)	19.9 (11.2-28.6)	40.7 (28.0-57.3)
Hazard ratio (95% CI)
Unadjusted	1	0.50 (0.29-0.89)	1.04 (0.63-1.71)
Model 1*	1	1.04 (0.56-1.94)	1.99 (1.07-3.70)

^*Model 1 is adjusted for age (linear), center-race interaction (5-level), sex, educational attainment (<high school, high school, college or higher), and cigarette smoking (current, former, never).

^**Model 2 is additionally adjusted for marital status, LDL-C (quadratic), diet score (linear), physical activity (linear), and prevalence of coronary artery disease and diabetes at baseline.

Associations of light-to-moderate drinking versus abstention were in opposite directions in whites compared with blacks and confidence intervals overlapped considerably and therefore we cannot conclude that hazard ratios differ by sex-race group (Supplemental Figure I; p=0.5). Hazard ratios ranged from 0.78 (0.56-1.10) in white women to 1.20 (0.75-1.92) in black men.

ICH incidence rates ranged from 20 per 100,000 person-years among light drinkers to 41 among moderate-to-heavier drinkers. We found no clear association of light drinking compared with abstention (HR=1.04, 0.56-1.94) after adjustment for age, race, sex, smoking status and education (Table 2). Moderate-to-heavier drinking, however, was associated with higher ICH rates compared with abstention (HR=1.99, 1.07-3.70); this estimate was unchanged when heavier drinkers were removed. The precision of these estimates was low because of small numbers of events, which also precluded adjustment for additional lifestyle factors. Effect estimates for total stroke were similar to those for IS alone: HR_light=0.98, 0.80-1.20; HR_moderate=1.13, 0.91-1.42; and HR_heavy=1.36, 0.97-1.91.

Results from models with quadratic splines representing alcohol intake did not support a J-shaped relationship (Figure 1); higher-order spline terms were not significant, although these analyses were under-powered to estimate dose-response relationships. The log-hazard ratio of IS was roughly linear across intake (β=0.06 for a 1 drink-per-week increase; HR=1.06, 0.99-1.13; p=0.1) and also non-significant. Additional quadratic (p=0.3) and cubic terms (p=0.9) were not statistically significant compared with the linear model.

Figure 1.

Dose-response relationship between midlife alcohol consumption and IS estimated with quadratic splines. Shading indicates 95% confidence bands. Knots were placed at 0.5, 3, and 17 drinks/week. Point estimates and 95% confidence intervals from categorical analysis are overlaid on the curve at the median of each category.

More than one-quarter of the participants died over follow-up, ranging from 24% in light to 42% in heavier drinkers. The estimated HR_SD account for this underlying mortality and reflect the relative cumulative incidence in our population. As expected, effect estimates were attenuated slightly for heavy drinkers; light and moderate alcohol consumption were not associated with reduced IS risk compared with abstention and moderate intake may increase ICH risk (Table 3). Lastly, we explored the impact of former versus never drinking on stroke. Estimates were non-significant with wide confidence intervals; interpretation of these estimates is difficult because of heterogeneity in consumption levels among former drinkers.

TABLE 3.

Cause-specific and subdistribution hazard ratios and 95% confidence intervals (CI) for the association of alcohol consumption and IS and ICH

	Alcohol Consumption, drinks per week
	Lifetime abstainer	≤3	4-17	18+
Ischemic stroke *
Hazard ratio (95% CI)
Cause-specific	1	0.98 (0.79-1.21)	1.06 (0.84-1.34)	1.31 (0.92-1.86)
Subdistribution	1	0.97 (0.79-1.21)	1.06 (0.84-1.35)	1.19 (0.83-1.72)
	Lifetime abstainer	≤3	4+
Intracerebral hemorrhage *
Hazard ratio (95% CI)
Cause-specific	1	1.04 (0.56-1.94)	1.99 (1.07-3.70)
Subdistribution	1	1.07 (0.55-2.05)	1.95 (1.00-3.81)

^*IS and ICH models are adjusted for covariates listed in Model 2 and Model 1, respectively of Table 2

CONCLUSIONS

We did not find a protective effect of light-to-moderate mid-life alcohol consumption on IS or ICH in this analysis of a bi-racial population-based cohort of US adults. Heavier intake tended to increase rates of IS and ICH compared with abstention, though confidence intervals were wide. The dose-response relationship we estimated for IS was imprecise, and did not support a clear J-shaped or linear relationship.

Alcohol consumed moderately in mid-life may lower IS risk through beneficial alterations in vascular risk factors including HDL-cholesterol, blood pressure, platelet aggregation, inflammatory markers and insulin sensitivity compared with no drinking.^{7, 26-28} In contrast, high doses of alcohol have well-established deleterious effects including elevated blood pressure, inflammation, and development of atrial fibrillation. Low-dose alcohol may also increase the risk for hemorrhage through hemostatic changes that promote bleeding. Dose-specific effects may differ by sex; women attain higher blood alcohol levels than men because of different body composition and alcohol metabolism.²⁹

A J-shaped relationship between alcohol and ischemic stroke is frequently reported in meta-analyses.^{7, 8, 13-15} Consumption of 1-2 drinks/day was associated with 28% lower risk and >4 drinks per day with 69% increased risk.⁷ Meta-analyzed results may be limited by inclusion of studies with non-validated stroke events, no adjustment for lifestyle factors, and inclusion of causal intermediates (e.g. blood pressure and HDL-C) in regression models. Our results, based on well-validated events with adjustment for important confounders, suggest no clear association between alcohol and stroke until heavier intake levels. Inconsistencies in estimates across studies could be due to differential distributions of etiologic subtypes in these cohorts coupled with a different mechanistic role of alcohol in their etiology (i.e. larger protective effect for thrombotic vs. cardioembolic strokes). Differences may also result from heterogeneity according to drinking pattern or sex-race or from measurement and selection biases.

Stronger protective effects of low-dose alcohol are reported for women compared with men (HR=0.66, 95% CI 0.61-0.71 vs. 0.80, 0.67-0.96).^{7, 8} Women consuming <2 drinks/day in the Nurses’ Health Study (a primarily white cohort) had a 12-18% lower risk of IS compared with non-drinkers.¹⁴ This aligns with results for white, but not black, women in the ARIC study. Our results for men were similar to those reported by the Health Professionals Follow-up Study that found no association for <1 drink/day and slightly elevated risk of ≥1 drinks/day.¹² We noted non-significantly higher HRs for blacks compared with whites that could be explained by different drinking patterns between whites and blacks.³⁰ Evidence suggests that moderate quantities of alcohol may be beneficial when consumed at moderate, but not high, frequency.¹²

Meta-analyzed data indicate that ICH risk increases log-linearly with increasing alcohol consumption for men, with possible J-shaped curves for women.^{6, 7, 14} Consumption of ≤2 drinks/day is associated with 12-24% lower hemorrhage risk compared with abstention.^{6, 7, 14} We did not find evidence of a protective effect of light drinking in our population. ICH rates were increased even at moderate drinking levels compared with abstention. Our results, however, were limited by small numbers of events.

Our results should be interpreted in light of several limitations. Participants may under-report alcohol consumption leading to misclassification. While we were unable to quantify errors, construct and rank-order validity was supported by positive correlations of alcohol with both HDL-C and blood pressure. Residual confounding is possible. We had low power to estimate precise effects, particularly among heavier drinkers and for ICH. Finally, race-specific results may not generalize to the U.S. population outside of the ARIC communities.

Strengths of our study include a prospective study design with >20 years of follow-up, a bi-racial population, and robust stroke ascertainment. Alcohol consumption was assessed using a validated instrument with beverage-specific questions (thus reducing under-reporting) that differentiated never from former drinkers. We had rich covariate data that permitted adjustment for lifestyle factors, smoking, and SES.

Public health recommendations for alcohol consumption must consider both its benefits and risks. While light-to-moderate intake may reduce the risk of some cardiovascular outcomes, other harmful effects exist even at low doses (e.g., dependency, cancer). As such, the American Heart Association does not recommend initiation of drinking for disease prevention.³¹ Our results support this recommendation. We found no significant risk reduction for IS or ICH with light-to-moderate mid-life alcohol consumption and increased risks at heavier intake levels. Understanding the alcohol-stroke relationship would be advanced by assessing dose-dependent exposure measurement errors, updating meta-analyses to include only high-quality studies and to explore modification by drinking pattern, etiologic subtype, and sex-race.